Structure Prediction and 3D Modeling of Single Stranded DNA from Sequence for Aptamer-Based Biosensors

Abstract

Aptamers consist of short oligonucleotides that bind specific targets. They provide advantages over antibodies along different lines, including robustness, low cost, and reusability. Their relatively simple chemical structure allows the insertion of electrochemical or fluorescent reporter molecules as well as surface-binding agents in specific locations, which have been recently exploited for the development of aptamer-based biosensors and a number of direct detection strategies. Mainstream use of these devices, however, still requires significant improvements in optimization for consistency and reproducibility. DNA aptamers are more stable than their RNA counterparts for biomedical applications but have the disadvantage of lacking the wide array of computational tools for structural prediction currently available for single stranded RNA. Here, we present the first approach to predict from sequence the three-dimensional structures of single stranded DNA required for aptamer applications. The approach consists of a pipeline that integrates sequentially building ssDNA secondary structure from sequence, constructing equivalent 3D ssRNA models, transforming the 3D ssRNA models into ssDNA 3D structures, and refining the resulting ssDNA 3D structures. Through this pipeline, our approach faithfully predicts the representative structures available in the Nucleic Acid Database and Protein Data Bank databases. Our results, thus, open up a much-needed avenue for integrating DNA in the computational analysis and design of aptamer-based biosensors.